Persisting multilineage transgene expression in the clonal progeny of a hematopoietic stem cell
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Persisting multilineage transgene expression in the clonal progeny of a hematopoietic stem cell. / Li, Z; Fehse, B; Schiedlmeier, B; Düllmann, J; Frank, O; Zander, A R; Ostertag, W; Baum, C.
in: LEUKEMIA, Jahrgang 16, Nr. 9, 09.2002, S. 1655-63.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Persisting multilineage transgene expression in the clonal progeny of a hematopoietic stem cell
AU - Li, Z
AU - Fehse, B
AU - Schiedlmeier, B
AU - Düllmann, J
AU - Frank, O
AU - Zander, A R
AU - Ostertag, W
AU - Baum, C
PY - 2002/9
Y1 - 2002/9
N2 - Many applications of hematopoietic gene therapy require selection for clones with active transgene expression. However, it was unclear whether the clonal progeny of a retrovirally transduced hematopoietic stem cell would be capable of maintaining transgene expression through serial repopulation and multilineage differentiation. Such investigations require simultaneous analyses of clonality, multilineage activity and transgene copy numbers. Using a mouse model, the present study demonstrates that a single hematopoietic stem cell expressing a marker gene from one or two insertions of a simple retroviral vector actively maintains multilineage transgene expression in the vast majority (80-99%) of bone marrow and peripheral blood cells. Gene expression persisted through serial transplantations for at least 97 weeks post gene transfer and was observed in the lymphoid (B, T and NK cells), myeloid (CD11b(+), Gr-1(+)), erythroid (Ter119(+), mature red blood cells) and megakaryocytic (as indicated by platelets) progeny. Therefore, a single immunoselection for hematopoietic stem cells expressing the transgene in vivo was sufficient to establish a completely chimeric hematopoiesis. These observations imply that the retroviral vectors used in this study contain cis-elements that mediate expression through massive clonal expansion and multilineage differentiation, provided the insertion occurred in genetic loci permissive for expression in hematopoietic stem cells.
AB - Many applications of hematopoietic gene therapy require selection for clones with active transgene expression. However, it was unclear whether the clonal progeny of a retrovirally transduced hematopoietic stem cell would be capable of maintaining transgene expression through serial repopulation and multilineage differentiation. Such investigations require simultaneous analyses of clonality, multilineage activity and transgene copy numbers. Using a mouse model, the present study demonstrates that a single hematopoietic stem cell expressing a marker gene from one or two insertions of a simple retroviral vector actively maintains multilineage transgene expression in the vast majority (80-99%) of bone marrow and peripheral blood cells. Gene expression persisted through serial transplantations for at least 97 weeks post gene transfer and was observed in the lymphoid (B, T and NK cells), myeloid (CD11b(+), Gr-1(+)), erythroid (Ter119(+), mature red blood cells) and megakaryocytic (as indicated by platelets) progeny. Therefore, a single immunoselection for hematopoietic stem cells expressing the transgene in vivo was sufficient to establish a completely chimeric hematopoiesis. These observations imply that the retroviral vectors used in this study contain cis-elements that mediate expression through massive clonal expansion and multilineage differentiation, provided the insertion occurred in genetic loci permissive for expression in hematopoietic stem cells.
KW - Animals
KW - Antigens, CD34/genetics
KW - Bone Marrow Cells/metabolism
KW - Cell Lineage/physiology
KW - Chimera
KW - Colony-Forming Units Assay
KW - Female
KW - Gene Dosage
KW - Gene Silencing
KW - Gene Transfer Techniques
KW - Green Fluorescent Proteins
KW - Hematopoiesis/physiology
KW - Hematopoietic Stem Cell Transplantation
KW - Hematopoietic Stem Cells/physiology
KW - Humans
KW - Luminescent Proteins/metabolism
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Retroviridae/genetics
KW - Transduction, Genetic
KW - Transfection
KW - Transgenes/physiology
U2 - 10.1038/sj.leu.2402619
DO - 10.1038/sj.leu.2402619
M3 - SCORING: Journal article
C2 - 12200677
VL - 16
SP - 1655
EP - 1663
JO - LEUKEMIA
JF - LEUKEMIA
SN - 0887-6924
IS - 9
ER -